This research proposal focuses on the hypothesis that Fas- mediated apoptosis contributes to oxidative injury of human RPE (hRPE) and thereby could contribute to age-related macular degeneration (ARMD). Previous research has shown that loss of RPE is a pivotal early event in ARMD and circumstantial evidence indicates that oxidative mechanisms are involved. Recent studies from this research group have shown that oxidant-induced cell death in hRPE may involve 2 mechanisms, activation of mitochondria-mediated apoptosis and activation of Fas-mediated apoptosis. The proposed research will determine 1) whether activation of Fas is a principal mechanism acting upstream of mitochondria in oxidant-induced apoptosis in hRPE, 2) whether physiologic processes associated with aging potentiate cell death mediated by Fas in cultured hRPE and 3) whether there is a sufficient concentration and variation in human blood levels of FasL (sFasL in plasma and FasL in monocytes) to warrant clinical studies of the potential association between blood FasL and ARMD. Although the successful completion of these aims cannot be expected to establish a mechanism for ARMD, they will provide important information on the possibility that Fas-mediated apoptosis plays a central role in the disease process.